Human motor neurons derived from induced pluripotent stem cells are susceptible to SARS-CoV-2 infection

Abstract

IntroductionCOVID-19 typically causes Q7 respiratory disorders, but a high proportion of patients also reports neurological and neuromuscular symptoms during and after SARSCoV-2 infection. Despite a number of studies documenting SARS-CoV-2 infection of various neuronal cell populations, the impact of SARS-CoV-2 exposure on motor neuronal cells specifically has not been investigated so far.MethodsThus, by using human iPSC-derived motor neurons (iPSC-MNs) we assessed: (i) the expression of SARS-CoV-2 main receptors; (ii) iPSC-MN infectability by SARS-CoV-2; and (iii) the effect of SARS-CoV-2 exposure on iPSC-MN transcriptome.ResultsGene expression profiling and immunofluorescence (IF) analysis of the main host cell receptors recognized by SARS-CoV-2 revealed that all of them are expressed in iPSC-MNs, with CD147 and NRP1 being the most represented ones. By analyzing SARS-CoV-2 N1 and N2 gene expression over time, we observed that human iPSC-MNs were productively infected by SARS-CoV-2 in the absence of cytopathic effect. Supernatants collected from SARS-CoV-2-infected iPSC-MNs were able to re-infect VeroE6 cells. Image analyses of SARS-CoV-2 nucleocapsid proteins by IF confirmed iPSC-MN infectability. Furthermore, SARS-CoV-2 infection in iPSCMNs significantly altered the expression of genes (IL-6, ANG, S1PR1, BCL2, BAX, Casp8, HLA-A, ERAP1, CD147, MX1) associated with cell survival and metabolism, as well as antiviral and inflammatory response.Discussion:These results suggest for the very first time that SARS-CoV-2 can productively infect human iPSC-derived MNs probably by binding CD147 and NRP1 receptors. Such information will be important to unveil the biological bases of neuromuscular disorders characterizing SARS-CoV-2 infection and the so called long-COVID symptoms.

Inflammatory Response and Defects on Myelin Integrity in the Olfactory System of K18hACE2 Mice Infected with SARS-CoV-2

“…However, although the neuroinvasive potential of SARS-CoV-2 was proposed at the outset of the pandemic ( L. Mao et al, 2020 ; Li et al, 2020 ; Moriguchi et al, 2020 ; Varatharaj et al, 2020 ), solid evidence to demonstrate neuronal infection in the human tissue remains in dispute. Several reports present compelling evidence of neuronal infection ( Paniz-Mondolfi et al, 2020 ; Ramani et al, 2020 ; Burks et al, 2021 ; de Melo et al, 2021 ; Meinhardt et al, 2021 ; Song et al, 2021 ; Cappelletti et al, 2023 ; Yang et al, 2024 ), while others reported no direct infection of neurons ( Brann et al, 2020 ; Pellegrini et al, 2020 ; Butowt et al, 2021 , 2023 ; Khan et al, 2021 ; Finlay et al, 2022 ; Zazhytska et al, 2022 ; Luczo et al, 2024 ). Similarly, studies in laboratory animals report both the presence ( Golden et al, 2020 , 2022 ; Oladunni et al, 2020 ; Zheng et al, 2021 ; Beckman et al, 2022 ; Olivarria et al, 2022 ; Seehusen et al, 2022 ; Vidal et al, 2022 ; Yu et al, 2022 ; Villadiego et al, 2023 ; Shimizu et al, 2024 ) and absence ( Bryche et al, 2020 ; Ye et al, 2021 ; Kishimoto-Urata et al, 2022 ; Verma et al, 2022 ) of neuronal infection.…”

Post COVID-19 Reflections and Questions: How Prepared Are We for the Next Pandemic?

“…Furthermore, this short treatment period also allowed for the rapid approval of drug trials due to the emergency, life-threatening COVID-19 pandemic conditions [13]. Similar approaches have also been considered for the development of drugs for the treatment of the severe acute respiratory syndrome and other life-threatening side effects of the virus, affecting other systems in addition to the respiratory system, such as the cardiovascular, gastrointestinal, nervous, immune and hematopoietic systems [20][21][22][23][24][25]. A different approach has been considered for the development of other drugs that are related to each of the different stages of COVID-19 and also for the "long COVID" side effects [11,[26][27][28][29][30][31][32][33].…”